Technical Field and Disclosure of Invention
[0001] This invention relates to novel and therapeutically useful 4-amino-1,2,3,4-tetrahydro-2-naphthoic
acid derivatives of the formula:
and salts thereof, wherein X is halogen atom, i.e. fluorine, chlorine, bromine or
iodine; n is 1 or 2; R
1 is hydroxy group, lower alkoxy group, e.g. methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, or amino group; and R
2 is hydrogen atom, lower alkanoyl group, e.g. acetyl, propionyl, butyryl, isobutyryl,
etc. or carbamoyl group.
[0002] Japanese Patent Publication No. 43-22097 (1968), Chem. Pharm. Bull., 14, 324 (1966)
and J. Med. Chem., 21, 1105 (1978) make mention of.compounds useful as an intermediate
for the synthesis of a certain kind of analgesics, which compounds are represented
by the formula:
wherein X' is hydrogen atom or methoxy group, R
1' is hydroxy group or C
1-
4-alkoxy group, and R
2' is hydrogen or C
1-
4-alkanoyl group.
[0003] The present inventors have synthesized a variety of the derivatives having gamma-aminobutyric
acid (hereinafter abbreviated as GABA) moiety in their structure and investigated
into their usefulness. As a result, this invention has been accomplished on the basis
of the new finding that the compounds of the invention unexpectedly have potent diuretic
and blood pressure lowering activity, although they show little protecting effects
on the functions in which only the central nervous system participates such as convulsions
or fatal convulsions induced by a GABA antagonist such as bicuculline or picrotoxin.
[0004] To the contrary, with the aforementioned known compounds these activity are extremely
weak or substantially are not found.
[0005] The compounds of formula (I) wherein R
2 is hydrogen can be produced for example by the following Methods 1 to 3:
Method 1
[0006] Method of reducing an oxime compound of the formula:
wherein X, n and R
1 are the same as defined above. Preferably, catalytic reduction is carried out in
the presence of a metallic catalyst such as Raney nickel, platinum oxide or palladium
carbon in an inert solvent, preferably a C
1-
4-alkanol such as methanol, ethanol or the like or a C
1-4-alkanoic acid such as acetic acid, if desired in the presence of ammonia for prevention
of possible polymerization, at a temperature of room temperature to 150°C, preferably
50 to 100°C under normal pressure or 50 to 150 atm of hydrogen. Here, hydrogen or
hydrazine may be used as a hydrogen source. Otherwise, the reduction may be carried
out by the use of metallic sodium in liquid ammonia containing methanol or by the
use of both hydrochloric acid or acetic acid and zinc or tin.
Method 2
[0007] Method of subjecting a compound of the formula:
to ammonolysis in water or C
1-4-alkanol, wherein X, n and R
1 are the same as defined above, and Y is halogen atom, methylsulfonyloxy group, p-tolylsulfonyloxy
group or the like as the reactive residue.
Method 3
[0008] Method of subjecting a compound of the formula:
to Leuckart reaction, wherein X, n and R
1 are the same as defined above. That is, a compound of formula (IV) and urea, ammonium
formate or the like undergo fusion reaction in the presence of formic acid at 150-200°C
and the resulting product is hydrolyzed to give the intended compounds.
[0009] The compounds of formula (I) wherein R' is hydrogen are allowed to react with a reactive
derivative of C
1-
4-alkanic acid such as acid halide, acid anhydride or the like to give the compounds
of formula (I) wherein R
2 is C
1-
4-alkanoyl. They are allowed to react with potassium cyanate or sodium cyanate in an
. aqueous C
1-
4-alkanol to give the compounds of formula (I) wherein R
2 is carbamoyl.
[0010] The compounds of formula (I) wherein R
1 is hydroxy group are allowed to esterify with C
l-
4-alkanol in the presence of mineral acid such as hydrochloric acid or sulfuric acid
to give the compounds of formula (I) wherein R
1 is C
1-
4-alkoxy. The ester compounds thus obtained or their free carboxylic acids are allowed
to react with ammonia to give the compounds of formula (I) wherein R
1 is amino.
[0011] The N-C
l-
4-alkanoyl compounds and the ester compounds or the amido compounds each of formula
(I) are subjected to hydrolysis to give, reversely, the amino compounds and the free
carboxylic acids of formula (I), respectively.
[0012] The compounds of formula (I) of this invention produced in this way are present in
the form of diastereoisomers, with their tetralin ring containing asymmetric carbon
atoms at the 2- and 4-positions.
[0013] When the mixture of the diastereoisomers is fused under heating at 60 to 200°C, preferably
100 to 140°C, the 2,4-cis isomer (simply referred to as "cis-isomer") causes ring
closure to form 1,4-methano-2- benzazepin-3-one derivative of the formula:
wherein X and n are the same as above. Since the compound of formula (V) is neutral,
the 2,4-trans isomer (simply referred to as "trans-isomer") can be isolated by the
extraction with acid or alkali. The compounds of formula (V) can be converted, upon
hydrolysis by acid or alkali, into the cis-isomer of the amino-acid.
[0014] The cis-isomer and the trans-isomer thus separated are respective racemates, and
the racemates can be separated into respective optically active isomers, for example
by optically resolving the ester compounds with an optically active carboxylic acid,
e.g. tartaric acid, dibenzoyltartaric acid, camphorsulfonic acid, diacetyltartaric
acid, phenylsuccinic acid, mandelic acid, malic acid, lactic acid, etc. or the amino-protected
carboxylic acid compound with an optically active base (e.g. natural alkaloid such
as brucine, quinine, cinchonidine, etc., optically active a-phenethylamine, a-amino
acid ester, etc.).
[0015] Where a carboxylic acid compound of formula (II), (III) or (IV) optically active
at the 2-position is used, respective optical isomers can be obtained only through
the foregoing procedure of separation into the cis-isomer and the trans-isomer.
[0016] The compounds (I) of the invention may be, if desired, treated with acid (e.g. inorganic
acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or organic
acid such as acetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, citric
acid, etc.) or with inorganic base (e.g. sodium hydroxide, sodium bicarbonate, potassium
hydroxide, calcium hydroxide, etc.) to form their acid or base adducts.
[0017] As will be apparent from the description above, the compounds (I) of this invention
include all of the diastereoisomers, cis-isomers, transisomers and optically active
isomers and salts of them.
[0018] The diuretic activity of the compounds (I) according to this invention will be shown
hereinbelow. The transisomers have more potent activity than the cis-isomers.
Test Method
[0019] According to the method of Lipschitz et al (W. L. Lipschitz, Z. Haddian, A. Kerpsser
: J. Pharmacol. Exp. Therap., 79, 97 (1943)), groups each of 6 male Wistar rats (weighing
180 to 220 g) were used. In preconditioning, they were not fed with any food for 18
hours and further with any food and water for 3 hours. Test group of the rats was
orally administered with a solution or suspension of the test compounds of this invention
in isotonic saline at a dosage of 25 ml/kgand was placed in metabolism cages, and
urine of them was collected in the course of 6 hours.
[0020] The diuretic activity is calculated by the following equation in terms of increment
percentage of the test group to control group:
Results
[0021] Under the same test conditions above, 4-amino-1,2,3,4-tetrahydro-2-naphthoic acid
hydrochloride, methyl trans-4-amino-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
ethyl trans-4-amino-6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthoate hydrochloride did
not show any results significantly different from the control group. With GABA per
se, the diuretic activity could not be found even at a high dosage of 1000 mg/ kg.
[0022] Blood pressure lowering action due to the compound of Example 1 a which is typical
of this invention is shown in the following:
Test Method
(1) Experiment with Spontaneous Hypertensive Rats (SHR)
[0023] Spontaneous hypertensive male rats (SHR) of 28 to 30 weeks age were used for the
experiment and blood pressure was measured according to tail compressing method. These
rats were preliminarily divided into control group and test group (six rats/one group)
so that both the groups have the same mean blood pressure.
[0024] A suspension of the test compounds in 0.5% methylcellulose solution was administered
orally to the test group at a dosage of 2 ml/kg and after 1, 5, 7 and 9 hours blood
pressure was measured. Dosage required for lowering the blood pressure value before
the administration by 20 mm Hg was determined.
(2) Experiment with DOCA Hypertensive Rats
[0025] According to the method of Willard, male Wistar rats of 8 weeks age were made DOCA
(deoxycorticosterone acetate) hypertensive rats by operation and among them, rats
whose blood pressure values after 6 weeks had reached upward of 150 mm Hg were used
as test animal.
[0026] The experiment was carried out in the same conditions as those of SHR above. Results
[0027] In both the Experiments, the blood pressure lowering action was gradually and slowly
exhibited and its maximum effect was exerted 7 to 9 hours after the administration
of the test compound.
[0028] The compounds of formula (I) of this invention can be administered orally or parenterally
as pharmaceutical composition by the combination with a suitable, conventional pharmaceutically
acceptable carrier. The pharmaceutical composition may be the form of tablets, capsules,
granules, powders, injectable solutions or the like.
[0029] The daily dose of the compounds (I) for human adults ranges usually from about 10
mg to about 500 mg for oral administration in single dose or multiple doses, but may
vary depending on the age, weight and/or conditions of disease to be treated and response
to the medication.
[0030] The invention will be hereinafter described more concretely by the following examples,
but they are not to be construed as limiting the invention.
Example 1
[0031]
(a) A solution of 265 g of ethyl 7,8-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate
(m.p. 133-135°C) in 1 1 of ethanol is charged into 31-autoclave and 130 ml of 12%
ethanolic ammonia and 27 g of Raney nickel are added thereto to reduce with hydrogen
under pressure of 65 atm at an inner temperature of 75°C. The hydrogen uptake is completed
in about 3 hours, and then the whole is allowed to cool. The catalyst is filtered
off and the filtrate is concentrated. Ethyl acetate is added to the residue and cooled.
Crystals are deposited and collected by filtration to give 75 g of 6,7-dichloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,
m.p. 196-200°C, which is ring-closure product of the foregoing cis-isomer. The filtrate
solution is washed with water once, dried and concentrated under heating on oil bath
at 130°C for 3 hours. After cooling, ethyl acetate is added and the deposited crystals
are collected by filtration to recover an additional 14 g of the ring-closure isomer.
The filtrate solution is diluted with 1 I of ethyl acetate and 150 ml of 20% aqueous
hydrochloric acid is added with stirring, whereupon white needles separate out. The
crystals are collected by suction filtration to give 76 g of crude ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate
hydrochloride. The aqueous layer of the filtrate solution is separated, the organic
layer is extracted with water several times and the aqueous layers combined are saturated
with sodium chloride. An additional 23 g of crystalline product is recovered. The
product, when recrystallized from ethanol, shows a m.p. of 249-251°C (decomposition).
(b) Ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate, when optically
resolved by dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid, affords optically
active dextro- and levo-isomers, respectively.
[0032] Hydrochloride of dextro-isomer . m.p. 209-213°C [a]
D = + 38.6 (1%, methanol)
[0033] Hydrochloride of levo-isomer m.p. 208-213°C [a]
D = - 37.4 (1%, methanol)
Example 2
[0034] A suspension of 29 g of 6,7-dich)oro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one
in 300 ml of 20% hydrochloric acid is hydrolyzed by heating with stirring for 40 hours.
After cooling, crystals are precipitated and collected by filtration to give 32 g
of crude cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride.
To the crude product is added 500 ml of ethanol, and dry hydrochloric acid gas is
introduced gently with stirring under reflux for 8 hours. After cooling, crystals
are deposited, separated by filtration and recrystallized from 95% ethanol to give
29 g of ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride
having a m.p. of 239-245°C (decomposition) as white needles.
Example 3
[0035] A solution of 60 g of methyl 6,7-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate
in 300 ml of methanol and 300 ml of 10% ammonia-methanol is hydrogenated at 60 atm
of hydrogen in the presence of Reney nickel. Heating is conducted at 70-80°C with
stirring for 7 hours. After cooling, the catalyst is filtered off and the solvent
is distilled off. Acetone is added to the semi-solid residue and cooled. The precipitated
crystals are collected by filtration to give 17 g of 7,8-dichioro-1,4-methano-2,3,4,5-tetrahydro-1H-2-
benzazepin-3-one, m.p. 215-217°C. The mother liquor is concentrated, heated at 100-120°C
for 2 hours and cooled followed by crystallization from acetone. Upon filtration,
additional 3 g of ring-closure product is obtained. The mother liquor is concentrated,
and ethyl acetate and 100 ml of 10% aqueous hydrochloric acid are added and stirred
well. White needles are deposited and collected by filtration to give 10 g of methyl
trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride in the crystalline
form. From the mother liquor, a further 3 g of the product is recovered. The product,
upon recrystallization from methanol, gives white needles having a m.p. of 262-263°C
(decomposition).
Example 4
[0036] Into a solution of 3.6 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate
hydrochloride in 50 ml of methanol and 15 ml of 28% aqueous ammonia, ammonia gas is
blew at 30-40°C for 8 hours. The solvent is distilled off and water is added. The
precipitated crystals are separated by filtration and dissolved in methanol and to
the solution is added methanolic hydrochloric acid. Crystals are deposited, separated
by suction filtration and recrystallized from methanol to give 1.6 g of trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthalene
carboxamide hydrochloride having a m.p. of above 280°C.
Example 5
[0037] To a solution of 1.5 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate
in 20 ml of pyridine is added 10 ml of acetic anhydride under ice-cooling, and the
reactant is allowed to stand overnight. The reaction solution is concentrated and
to the resulting residue is added water. Deposited crystals are separated by suction
filtration and recrystallized from ethanol to give 1.5 g of methyl trans-4-acetamide-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate,
m.p. 182-184°C.
Example 6
[0038] Into 100 ml of 50% methanol, 3.1 g of methyl trans-4-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate
hydrochloride is dissolved under warming, and to the solution is added dropwise a
solution of 1.2 g of potassium cyanate in 10 ml of water. After the dropwise addition,
the system is made to react at 60°C for 2 hours and cooled with ice. Deposited crystals
are separated by filtration, washed with water, and recrystallized from a mixture
of methanol and acetone to give 1.7 g of methyl trans-6,7-dichloro-4-ureido-1,2,3,4-tetrahydro-2-naphthoate
having a m.p. of 227-229°C.
[0039] The following compounds are produced in a similar manner to Examples 1 to 6.
7. Methyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p.
229-231°C.
8. Methyl cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride hydrate,
m.p. 218-219°C (decomposition)
9. Cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride, m.p. 269-271°C
(decomposition)
10. Ethyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p.
199-200°C
11. Trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride, m.p.
283-285°C
12. Methyl trans-4-amino-7-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p.
215-218°C
13. Cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride, m.p.
256-257°C
14. Trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride,
m.p. 283-285°C
15. Ethyl cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
m.p. 222-223°C
16. Ethyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
m.p. 234-236°C
17. Methyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
m.p. 247-250°C (decomposition)
18. Methyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
m.p. 240-2420C (decomposition)
19. Butyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride,
m.p. 163-167°C
20. Ethyl trans-4-amino-6-fluoro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p.
211-213°C
21. Ethyl trans-4-amino-6-bromo-1,2,3,4-tetrahydro-2-naphthoate.
[0040] The invention has been fully explained in the description and examples given above,
but any variations and modifications of it may be made without departing from the
spirit and scope of the invention.
Claims for the following Contracting State(s) : s: BE DE FR GB SE:
1. 4-Amino-1,2,3,4-tetrahydro-2-naphthoic acid derivatives of the formula:
or salts thereof, wherein X is halogen atom, n is 1 or 2, R
1 is hydroxy group, C
l-
4-alkoxy group or amino group, and R
2 is hydrogen atom, C
1-
4-alkanoyl group or carbamoyl group.
2. The compound as claimed in Claim 1, which is ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
3. The compound as claimed in Claim 1, which is ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
4. The compound as claimed in Claim 1, which is methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
5. The compound as claimed in Claim 1, which is methyl trans-4-amino-6-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
6. The compound as claimed in Claim 1, which is ethyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
7. The compound as claimed in Claim 1, which is methyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
8. The compound as claimed in Claim 1, which is methyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate.
9. A method of producing 4-amino-1,2,3,4-tetrahydro-2-naphthoic acid derivatives of
the formula:
or salts thereof, wherein X is halogen atom, n is 1 or 2, R
1 is hydroxy group, C
1-4-alkoxy group or amino group, and R
2 is hydrogen atom, C
1-
4-alkoxy group or carbamoyl group, by any of the following processes of:
(1) reducing an oxime compound of the formula:
wherein X, n and R1 are the same as defined above,
(2) subjecting a compound of the formula:
wherein X, n and R1 are the same as defined above, and Y is a leaving group to ammonolysis,
(3) subjecting a compound of the formula:
wherein X, n and R1 are the same as defined above, to Leuckart reaction,
(4) reacting said compound of formula (I) wherein R2 is hydrogen with reactive C1-4-alkanoic acid derivative,
(5) reacting said compound of formula (I) wherein R2 is hydrogen with potassium cyanate or sodium cyanate,
(6) esterifying said compound of formula (I) with a C1-4-alkanol,
(7) reacting said compound of formula (I) wherein R1 is hydroxy group or C1-4-alkoxy with ammonia,
(8) hydrolyzing said compound of formula (I) wherein R2 is C1-4-alkanoyl,
(9) hydrolyzing said compound of formula (I) wherein R1 is C1-4-alkoxy or amino,
(10) hydrolyzing a compound of the formula:
wherein X and n are the same as defined above.
10. A pharmaceutical composition comprising a therapeutically effective amount of
said compound as claimed in Claim 1 and a pharmaceutically acceptable carrier.
Patentansprüche für folgende(n) Vertragsstaat(en) : BE DE FR GB SE
1. 4-Amino-1,2,3,4-tetrahydro-2-naphthoesäure-Derivate der Formel
oder Salze davon, in der X ein Halogenatom bedeutet, n den Wert 1 oder 2 hat, R
1 eine Hydroxylgruppe, C
1-
4-Alkoxygruppe oder Aminogruppe darstellt und R
2 ein Wasserstoffatom, eine C
1-
4-Alkanoylgruppe oder Carbamoylgruppe bedeutet.
2. Verbindung nach Anspruch 1, nämlich trans-4-Amino-7,8-dichlor-1,2,3,4-tetrahydro-2-naphthensäureäthylester.
3. Verbindung nach Anspruch 1, nämlich cis-4-Amino-7,8-dichlor-1,2,3,4-tetrahydro-2-naphthoesäureäthylester.
4. Verbindung nach Anspruch 1, nämlich trans-4-Amino-6,7-dichlor-1,2,3,4-tetrahydro-2-naphthoesäuremethylester.
5. Verbindung nach Anspruch 1, nämlich trans-4-Amino-6-chlor-1,2,3,4-tetrahydro-2-naphthoesäuremethylester.
6. Verbindung nach Anspruch 1, nämlich trans-4-Amino-6,7-dichlor-1,2,3,4-tetrahydro-2-naphthoesäureäthylester.
7. Verbindung nach Anspruch 1, nämlich trans-4-Amino-7,8-dichlor-1,2,3,4-tetrahydro-2-naphthoesäuremethylester.
8. Verbindung nach Anspruch 1, nämlich cis-4-Amino-7,8-dichlor-1,2,3,4-tetrahydro-2-naphthoesäuremethylester.
9. Verfahren zur Herstellung von 4-Amino-1,2,3,4-tetrahydro-2-naphthoesäure-Derivaten
der Formel
oder von Salzen davon, in der X ein Halogenatom bedeutet, n den Wert 1 oder 2 hat,
R
1 eine Hydroxylgruppe, C
1-4-Alkoxygruppe oder Aminogruppe darstellt und R
2 ein Wasserstoffatom, eine C
1-
4-Alkoxygruppe oder carbamoylgruppe bedeutet, durch eines der folgenden Verfahren:
(1) Reduktion einer Oximverbindunq der Formel
in der X, n und R1 wie vorstehend definiert sind,
(2) Durchführung einer Amonolyse bei einer Verbindung der Formel
in der X, n und R1 wie vorstehend definiert sind und Y eine austretende Gruppe darstellt,
(3) Durchführung einer Leuckart-Reaktion mit einer Verbindung der Formel
in der X, n und R1 wie vorstehend definiert sind,
(4) Umsetzen einer Verbindung der Formel (I), in der R2 ein Wasserstoffatom bedeutet, mit einem reaktiven C1-4-Alkansäurederivat,
(5) Umsetzen einer Verbindung der Formel (1), in der R2 ein Wasserstoffatom bedeutet, mit Kaliumcyanat oder Natriumcyanat,
(6) Verestern der genannten Verbindung der Formel (I) mit einem C1-4-Alkanol,
(7) Umsetzen der genannten Verbindung der Formel (I), in der R1 eine Hydroxylgruppe oder eine C1-4-Alkoxygruppe bedeutet, mit Ammoniak,
(8) Hydrolysieren der genannten Verbindung der Formel (I), in der R2 eine C1-4-Alkanoylgruppe bedeutet,
(9) Hydrolysieren der genannten Verbindung der Formel (I), in der R1 eine C1-4-Alkoxy- oder Aminogruppe bedeutet,
(10) Hydrolysieren einer Verbindung der Formel
in der X und n wie vorstehend definiert sind.
10. Arzneimittel, umfassend eine therapeutisch wirksame Menge einer Verbindung nach
Anspruch 1 und einen pharamazeutisch verträglichen Träger.
Revendications pour l'(les) Etat(s) contractant(s) suivant(s) : BE DE FR GB SE
1. Dérivés d'acidé 4-amino-1,2,3,4-tétrahydro-2-naphtoïque de la formule:
ou leurs sels, dans laquelle X représente un atome d'halogène, n est égal à 1 ou 2,
R
1 représente un groupe hydroxy, un groupe alcoxy en C
1―C
4 ou un groupe amino et R
2 représente un atome d'hydrogène, un groupe alcanoyle en C
1―C
4 ou un groupe carbamoyle.
2. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
trans-4-amino-7,8-dichloro-1,2,3,4-tétrahydro-2-naphtoate d'éthyle.
3. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
cis-4-amino-7,8-dichloro-1,2,3,4-tétrahydro-2-naphtoate d'éthyle.
4. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
trans-4-amino-6,7-dichloro-1,2,3,4-tétrahydro-2-naphtoate de méthyle.
5. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
trans-4-amino-6-chloro-1,2,3,4-tétrahydro-2-naphtoate de méthyle.
6. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
trans-4-amino-6,7-dichloro-1,2,3,4-tétrahydro-2-naphtoate d'éthyle.
7. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
trans-4-amino-7,8-dichloro-1,2,3,4-tétrahydro-2-naphtoate de méthyle.
8. Composé suivant la revendication 1, caractérisé en ce qu'il est constitué par le
cis-4-amino-7,8-dichloro-1,2,3,4-tétrahydro-2-naphtoate de méthyle.
9. Procédé de production de dérivés d'acide 4-amino-1,2,3,4-tétrahydro-2-naphtoïque
de la formule:
ou de leurs sels, dans laquelle X représente un atome d'halogène, n est égal à 1 ou
2, R
1 représente un groupe hydroxy, un groupe alcoxy en C
1―C
4 ou un groupe amino et R
2 représente un atome d'hydrogène, un groupe alcoxy en C
1―C
4 ou un groupe carbamoyle, par l'un des procédés suivants:
(1) réduction d'un composé d'oxime de la formule:
dans laquelle X, n et R1 sont tels que définis précédemment,
(2) soumission d'un composé de la formule:
dans laquelle X, n et R1 sont tels que définis précédemment et Y représente un groupe partant, à une ammonolyse,
(3) soumission d'un composé de la formule:
dans laquelle X, n et R1 sont tels que définis précédemment, à une réaction de Leuckart,
(4) réaction du composé de formule (1) dans laquelle R2 représente de l'hydrogène avec un dérivé d'acide alcanoïque en C1―C4, réactif,
(5) réaction du composé de formule (1) dans laquelle R2 représente de l'hydrogène avec du cyanate de potassium ou du cyanate de sodium,
(6) estérification du composé de formule (1) par un alcanol en C1―C4,
(7) réaction du composé de formule (1) dans laquelle R1 représente un groupe hydroxy ou un groupe alcoxy en C1―C4 avec de l'ammoniac,
(8) hydrolyse du composé de formule (1) dans laquelle R2 représente un groupe alcanoyle en C1―C4,
(9) hydrolyse du composé de formule (1) dans laquelle R1 représente un groupe alcoxy en C1―C4 ou amino,
(10) hydrolyse d'un composé de la formule:
dans laquelle X et n sont tels que définis précédemment.
10. Composition pharmaceutique comprenant une quantité thérapeutiquement efficace
d'un composé suivant la revendication 1 et un support pharmaceutiquement acceptable.